Stereoselective Desymmetrization of gem-Diborylalkanes by “Trifluorination”

Article abstract of DOI:10.1002/chem.201901267

An efficient and general method for the chemoselective synthesis of unsymmetrical gem-diborylalkanes is reported. This method is based on a late-stage desymmetrization through nucleophilic “trifluorination”, providing chiral gem-diborylalkanes bearing a trifluoroborate group. The reaction offers a highly modular and diastereoselective approach towards the synthesis of gem-diborylcyclopropanes. The utility of the gem-diborylalkane building blocks was demonstrated by selective post-functionalization of the trifluoroborate group. These functionalizations include inter- and intra- Pd-catalyzed Suzuki–Miyaura coupling reactions.

Full text of DOI:10.1002/chem.201901267

A Journal of
Accepted Article
Title: Stereoselective Desymmetrization of gem-Diborylalkanes via
“trifluorination”
Authors: Ahmad Masarwa, Nivesh Kumar, and Reddy Rajasekhar
Reddy
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201901267
Link to VoR: http://dx.doi.org/10.1002/chem.201901267
Supported by

10.1002/chem.201901267
Chemistry - A European Journal
COMMUNICATION
Stereoselective Desymmetrization of gem-Diborylalkanes via
“trifluorination”
Nivesh Kumar, Reddy Rajasekhar Reddy, and Ahmad Masarwa*
Dedication ((optional))
Abstract: An efficient and general method for the chemoselective
synthesis of unsymmetrical gem-diborylalkanes is reported. This
method is based on a novel late-stage desymmetrization via
nucleophilic “trifluorination”, providing chiral gem-diborylalkanes
bearing a trifluoroborate group. The reaction offers a highly modular
Most of the gem-diborylalkanes bearing boronic acid or ester
groups (e.g., 10) are readily and commercially available.[10]
However, until very recently, there has been a lack of versatile
and efficient synthetic methods to access gem-borylalkanes
containing a trifluoroborate group (e.g., 11, Scheme 1D). To date,
there are only three reported methods for the synthesis of
secondary and tertiary gem-diborylalkanes of which one of the
groups is a trifluoroborate salt (3, 6, 9, Scheme 1).[11]
and
diastereoselective
approach
to
synthesize
gem-
diborylcyclopropanes. The utility of the gem-diborylalkane building
blocks was demonstrated by selective post-functionalization of the
trifluoroborate group. These functionalizations include inter- and intra-
Pd-catalyzed Suzuki−Miyaura coupling reactions.
gem-Diborylalkanes have recently emerged as a versatile class
of intermediates for preparing alkylboron compounds via
chemoselective
transformations.[1]
These
bisnucleophilic
compounds (termed sp3-geminated organodimetallics)[2] have
increasingly attracted much attention from synthetic chemists,[1a,
3]
particularly for constructing C–C bonds, e.g., the pioneering
work reported by Shibata in which he developed the first Pd-
catalyzed Suzuki−Miyaura cross-coupling of 1,1-diborylalkanes.[4]
Although many traditional approaches to the formation of C–C
bonds have been made available by using symmetrical gem-
diboryalkanes (e.g., 10 Scheme 1D),[5] methods for cross coupling
with unsymmetrical gem-diboryalkanes[6] via C–B bond activation
have not been satisfactorily addressed and could unveil new
opportunities for sequential bond formation. As such, advances
that accomplish the selective synthesis of unsymmetrical gem-
diborylalkanes and their transformation have the potential to
drastically improve the synthesis of organic molecules.
As a part of a general program to investigate the reactivity and
selectivity
of
gem-diborylalkanes
in
cross-coupling
transformations, we sought to prepare variants bearing a mono-
trifluoroborate-salt group (11) because, unlike boronic-esters, e.g.,
the Bpin group, mono-alkyl-trifluoroborate salts are known to be
easily activated and to undergo rapid transmetalation with
transition metal complexes.[7] In general, owing to their air-,
moisture-, shelf -, and thermal stability, as well as their occurrence
as free-flowing crystalline solids, mono-trifluoroborate-salts have
now become extremely popular reagents in synthesis.[8] Their
geminal analogues could offer new opportunities for reactivity.
This holds promise for expanding the range of boron-based cross-
coupling partners.[9]
Scheme 1. Overview for the synthesis of gem-diborylalkanes possessing
trifluoroborate salts.
In this context, Hall[11b, 12] reported the first preparation of a chiral,
enantioenriched 1,1-diboronyl-BF3K compound (3) through a
stepwise sequence of a copper-catalyzed conjugate addition of
the B2pin2 reagent to a 1,8-diaminonaphthalenyl (dan) 3-boronyl
enoate (1), followed by the reaction of the diboryl product (2) with
KHF2 (Scheme 1A). Similarly, in 2013, Yun[13] reported the
asymmetric synthesis of 1,1-diborylalkanes –BF3K (6) via regio-
and enantioselective copper(I)-catalyzed hydroboration of
borylalkenes (4) and the subsequent reaction of the product (5)
with KHF2 (Scheme 1B). Recently, in 2015, Molander[11a]
developed a method for the synthesis of an achiral class of
potassium 2-(trifluoroboratomethyl)-2,1-borazaronaphthalenes
(9). It is noteworthy that in order to obtain the BF3K group in 3, 6,
and 9, unsymmetrical gem-diborylalkanes bearing groups that
differed in reactivity were employed. For example, B(dan) is a
[*]
Dr. N. Kumar, Dr. R. R. Reddy, Dr. A. Masarwa
Institute of Chemistry, The Hebrew University of Jerusalem
Edmond J. Safra Campus, Jerusalem 91904 (Israel)
E-mail: Ahmad.Masarwa1@mail.huji.ac.il
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/chem.201901267
Chemistry - A European Journal
COMMUNICATION
protected boronic acid with lower reactivity[14] towards KHF2 as
compared to Bpin.
Although these commendable methods provide an elegant means
to access gem-diborylalkanes-BF3K, they are inherently limited as
(1) a large number of synthetic steps are required for their
preparation, (2) the use of environmentally unfriendly conditions,
e.g., KHF2 salts that etch glass, (3) the geminal-borylated carbon
in 11 can only be secondary or tertiary, (4) the geminal-borylated
carbon can only be replaced with alkyl groups, and (5) because a
special masked boron moiety is required, none of the existing
examples (3, 6, 9) use the more synthetically useful Bpin
group.[11b] Therefore, it became clear to us that a milder, more
efficient, and general methodology for simplifying the synthesis
of this class of gem-diboryalkanes was necessary.
[15]
To this end, we envisioned that a desymmetrization-based
approach of symmetrical gem-diborylalkanes could provide an
attractive solution (Scheme 1D). This goal could be accomplished
through a nucleophilic “trifluorination”[16] of gem-diborylalkanes,
as illustrated in Scheme 1D.[17] To achieve this aim, we sought to
employ conditions similar to those developed by Lloyd-Jones[18]
for the conversion of mono-boronic acids to trifluoroborate
potassium salts (Table 1). Initially, we examined the commercially
available gem-diborylmethane 10a. We were pleased to observe
11a as the sole product after a 5 min reaction time, under green
and mild conditions using either KF (entry 3), CsF (entry 5), or
TBAF (entry 9) as salts and an alkali metal sponge[18] (AMS), e.g.,
L-tartaric acid (entry 3) or citric acid (entry 7). The product was
obtained by precipitation, thus making product isolation rapid and
simple. Notably, product 11 was not obtained in the presence of
KHF2 or in the absence of AMS (entries 1–2). Moreover, the
selectivity and yield of 11 are not affected when an excess of MF
or AMS is used.
Table 1. Optimization of the reaction conditions[a-b]
Entry
MF
AMS
Yield[%]
Entry
MF
LiF
AMS
Yield[%]
13
0c
0
1
2
3
4
5
KHF2
KF
-
-
6
7
1
2
3
-
90
KF
KF
86
0
60
KF
1
1
1
8
FCd
AgF
9
TBAF
92
0c
CsF
10
KHF2
1
aReactions were carried out with 0.5 mmol of 10a and 1.025 mmol of AMS at
room temperature. bIsolated yields. cDecomposition of the starting material.
dFull conversion (FC) by 1H NMR.
Under the optimized conditions, the scope of the
desymmetrization reaction was examined (Scheme 2). Our
results show that we can selectively convert symmetrical gem-
diborylalkanes possessing alkyl, allyl, and aryl groups (up to 37
examples; 10) with secondary, tertiary, quaternary, and cyclic
groups into unsymmetrical trifluoroborated gemdiborylalkanes
(11b-ad). Moreover, when polyborylated compounds (10s, 10t,
and 10u) with two groups of gem-diboryls were used, the
“trifluorination” reaction chemoselectively desymmetrized both
sites to obtain 11t and 11u in good yields (Scheme 2B).
Scheme 2. Scope of the desymmetrization reaction via nucleophilic
“trifluorination” and rationalization for the selectivity.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901267
Chemistry - A European Journal
COMMUNICATION
However, when tetraborylated-ethane 10v was treated with
excess KF under the reaction conditions, 11v was obtained as a
single product. Upon scale-up, the KF/L-tartaric acid process was
equally as efficient and easy to carry out, thus generating, for
example, 1 g (90%) of 11a and 1 g (95%) of 11e (Scheme 2A).
Interestingly, when enantiopure gemdiboryl-proline 10m was
subjected to the reaction conditions using AMS (citric acid or L-
tartaric acid), a diastereoselectivity of 9:1 or 6:1, respectively (see
11m, Scheme 2A) was observed. This is likely the result of a
directing group effect for the tosyl-substituted proline.
unambiguously determined by a 2D-NMR NOESY and COSY
studies of 11a’-f’, and are consistent with a nucleophilic
“trifluorination” of the Bpin group on the less sterically hindered
face of the cyclopropane (Scheme 3, yellow-box).[23] Remarkably,
even when both faces of the cyclopropane are only slightly
sterically differentiated, e.g., Ph vs. Me in the trans-Ph-Me
cyclopropene 10c, the desymmetrization afforded product 11c’ as
a single diastereomer.
Having these valuable gem-diborylalkanes-BF3K (11) in hand, we
sought to demonstrate their synthetic utility in selective
transformations of the BF3M group as described in Scheme 4 and
5.[5j, 21b, 21c]
We believe that the mechanism[17-18] underlying the selectivity –
i.e., the observation of only the mono-BF3K product, while the
other boron substituent remains untouched – arises from “tandem”
in the fluorination step in which the first nucleophilic fluoride
attacks the vacant p-orbital of one of the boron centers of 12
(Scheme 2D), As a result, this fluorinated-boron (see 13)
becomes more electrophilic; hence, it forces the second and then
the third nucleophilic fluorides to attack only the originally
fluorinated boron center (12-15, Scheme 2D). Consequently, the
generated borate (BF3) moiety in (11) develops a partial negative
charge on the fluorides, and this partial negative charge stabilizes
the flanking Bpin group[19] toward subsequent attack by fluoride,
this stabilization may undergo through bridging fluoride structure
(see 11’, Scheme 2D).[20] [4]
In the case of R = Ph (in 10ae, 10ad), different conditions (i.e.,
11ad observed by 11BNMR using MeCN) had to be employed
because of the competing formation of a protodeboronation side
product (18, Scheme 2E).[5m, 21] This α-protodeboronation product
(18) is believed to arise from a scenario involving a discrete
doubly stabilized anion 16, which is protonated (or deuterated) at
the α-position,[5j] at which point the remaining Bpin group
undergoes trifluorination (Scheme 2E).
Scheme 4. Selective transformations of gem-Bpin-BF3K (11).
We were intrigued to observe that gem-diborylalkanes (11) could
be selectively converted, for the first time, into gem-diboryls
containing a boronic-acid moiety (B(OH)2) (see 19) through a
simple hydrolysis process as described in Scheme 4A.[24]
Gratifyingly, the gem-diborylalkanes-BF3K (11) can be directly
converted to different unsymmetrical gem-diborylalkanes (20-21,
Scheme 4B).[25]
Next, we tried the Pd-catalyzed inter- and intra-molecular Suzuki–
Miyaura cross coupling reaction on 11 (Scheme 5D). Such a cross
coupling reaction has been reported by Hall,[12] Yun,[13] and
Molander[11a] on different systems with gem-B(dan)-BF3K and
gem-azaborine-BF3K (Schemes 5A-C). However, no reports exist
for a reactant bearing the gem-Bpin-BF3M groups. These
compounds could offer an opportunity to overcome some
limitations of the previously reported methods including low
yield,[13] the need for coordinating groups,[12b] and for using a
strong bases such as KOH[4] (Schemes 5A-C, highlighted in red).
Subjecting 11b to the same reaction conditions reported by
Hall[12a] revealed 24b in negligible yield with many side products
e.g. the proto-deboronation product (Scheme 5E). However, 11l
without a coordinating carbonyl group affords the cross-coupling
product 24l with excellent yield (Scheme 5F).[5m] Moreover, the
intramolecular cross coupling reaction of 11f-2 afforded a clean
cyclization-product (24f-2) in good yield (Scheme 5G). However,
in comparison reactions with gem-Bpin-Bpin (10f-2) under the
same reactions conditions, or under the reaction conditions of
Scheme 3. Diastereoselective desymmetrization of gem-diborylcyclopropanes
10 (a’-f’) and the rationale for the diastereoselectivity.
Importantly, the desymmetrization process also displays
diastereoselectivity when applied to gem-diborylcyclopropanes
(10a’-f’, Scheme 3).[22] The structure and relative configuration of
the diastereomers of diborylatedcyclopropanes[22b] (11a’-f’) were
This article is protected by copyright. All rights reserved.

10.1002/chem.201901267
Chemistry - A European Journal
COMMUNICATION
Shibata[20] using KOH as a base, product 24f-2 was either not
obtained or observed with very low conversion along with the
proto-deboronation side product, respectively (Scheme 5H).
These observations demonstrate the critical role of the gem-Bpin-
BF3M unit of 11 on mild, efficient and selective transformations
without a need of a coordinating carbonyl group and providing a
selectively transformed into a collection of unsymmetrical gem-
diborylalkanes, which underline the usefulness of 11 as
intermediates for the general method for interconversion of gem-
boronic acid. Moreover, selective inter- and intra-molecular
Suzuki−Miyaura cross-coupling has been described using mild
conditions.
Studies to achieve an enantioselective
direct access to the product containing the Bpin functionality intact, desymmetrization transformation using chiral phase transfer
which is considered more synthetically useful than B(dan) and
azaborine groups.[12b]
catalyst,[26] as well as new transformations of gem-diborylalkanes
bearing a BF3M group are currently under investigation and will
be reported in due course.
Acknowledgments ((optional))
This research was supported by grants from the Azrieli
Foundation, The Casali Foundation, and The Hebrew University.
Keywords: gem-diborylalkanes • desymmetrization •
organotrifluoroborate-salts • cyclopropanes • Suzuki−Miyaura
cross-coupling
[1]
a) N. Miralles, R. J. Maza, E. Fernandez, Adv. Synth. Catal. 2018,
360, 1306-1327; b) C. Q. Wu, J. B. Wang, Tetrahedr Lett. 2018, 59,
2128-2140; c) M. Shimizu, T. Hiyama, P. Jpn. Acad. B-Phys. 2008,
84, 75-85.
[2]
[3]
I. Marek, J. F. Normant, Chemical Reviews 1996, 96, 3241-3267.
J. Kim, S. Park, J. Park, S. H. Cho, Angew. Chem. Int. Ed. 2016, 55,
1498-1501.
[4]
[5]
K. Endo, T. Ohkubo, M. Hirokami, T. Shibata, J. Am. Chem. Soc.
2010, 132, 11033-11035.
a) Y. Lee, J. Park, S. H. Cho, Angew. Chem. Int. Ed. 2018, 57,
12930-12934; b) K. Hong, X. Liu, J. P. Morken, J. Am. Chem. Soc.
2014, 136, 10581-10584; c) L. C. Cui, Z. Q. Zhang, X. Lu, B. Xiao,
Y. Fu, Rsc Adv 2016, 6, 51932-51935; d) M. V. Joannou, B. S.
Moyer, S. J. Meek, J. Am. Chem. Soc. 2015, 137, 6176-6179; e) C.
Hwang, W. Jo, S. H. Cho, Chem. Commun. 2017, 53, 7573-7576; f)
T. C. Stephens, G. Pattison, Org. Lett. 2017, 19, 3498-3501; g) D.
J. Blair, D. Tanini, J. M. Bateman, H. K. Scott, E. L. Myers, V. K.
Aggarwal, Chem. Sci. 2017, 8, 2898-2903; h) J. Kim, S. H. Cho,
ACS Catal. 2019, 9, 230-235; i) W. Sun, L. Wang, C. X. Xia, C. Liu,
Angew. Chem. Int. Ed. 2018, 57, 5501-5505; j) J. F. Hu, Y. Zhao, Z.
Z. Shi, Nat. Catal. 2018, 1, 860-869; k) N. Miralles, J. E. Gomez, A.
W. Kleij, E. Fernandez, Org. Lett. 2017, 19, 6096-6099; l) P. Zheng,
Y. Zhai, X. Zhao, T. Xu, Org. Lett. 2018; m) J. R. Coombs, L. Zhang,
J. P. Morken, J. Am. Chem. Soc. 2014, 136, 16140-16143; n) P. R.
Zheng, Y. J. Zhai, X. M. Zhao, T. Xu, Org. Lett. 2019, 21, 393-396;
p) C. Sun, B. Potter, J. P. Morken, J Am Chem Soc 2014, 136, 6534-
6537.
[6]
A. B. Cuenca, J. Cid, D. Garcia-Lopez, J. J. Carbo, E. Fernandez,
Org. Biomol. Chem 2015, 13, 9659-9664.
[7]
[8]
G. A. Molander, J. Org. Chem. 2015, 80, 7837-7848.
a) G. A. Molander, D. L. Sandrock, Curr. Opin. Drug. Disc. Devel.
2009, 12, 811-823; b) S. Darses, J. P. Genet, Chem. Rev. 2008,
108, 288-325; c) S. Darses, J. P. Genet, Eur. J. Org. Chem. 2003,
4313-4327.
Scheme 5. Selective inter- and intra-molecular Suzuki−Miyaura cross-coupling
of (11).
[9]
a) A. J. J. Lennox, G. C. Lloyd-Jones, Chem. Soc. Rev. 2014, 43,
412-443; b) G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40,
275-286.
In summary, we have developed the first desymmetrization
method of gem-diborylalkanes via nucleophilic “trifluorination”,
thus allowing the transformation of symmetrical gem-diBpin-
alkanes into gem-diborylalkanes containing trifluoroborate groups.
Compared to the reported methodologies involving KHF2, this
reaction constitutes a mild, general, and convenient approach to
synthesize a variety of differently substituted gem-diborylalkanes
possessing a trifluoroborate moiety. This process exhibits high
[10]
R. Nallagonda, K. Padala, A. Masarwa, Org. Biomol. Chem. 2018,
16, 1050-1064.
[11]
[12]
J. Amani, G. A. Molander, Org. Lett. 2015, 17, 3624-3627
a) J. C. H. Lee, R. McDonald, D. G. Hall, Nat. Chem. 2011, 3, 894-
899; b) J. C. H. Lee, H. Y. Sun, D. G. Hall, J. Org. Chem. 2015, 80,
7134-7143.
X. Feng, H. Jeon, J. Yun, Angew. Chem. Int. Ed. 2013, 52, 3989-
3992.
a) A. Coca, Boron reagents in synthesis, American Chemical
Society Distributed in print by Oxford University Press, Washington,
DC, 2016; b) H. Noguchi, K. Hojo, M. Suginome, J. Am. Chem. Soc.
2007, 129, 758-759.
X. P. Zeng, Z. Y. Cao, Y. H. Wang, F. Zhou, J. Zhou, Chem. Rev.
2016, 116, 7330-7396.
[13]
[14]
diastereoselectivity
when
gem-diborylcyclopropanes
are
[15]
desymmetrized. The trifluoroborate (in 11) groups can be
This article is protected by copyright. All rights reserved.

10.1002/chem.201901267
Chemistry - A European Journal
COMMUNICATION
[16]
[17]
J. A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119-6146.
a) H. Y. Sun, K. Kubota, D. G. Hall, Chem-Eur. J. 2015, 21, 19186-
19194.
[18]
A. J. J. Lennox, G. C. Lloyd-Jones, Angew. Chem. Int. Ed. 2012, 51,
9385-9388.
[19]
[20]
[21]
Q. Huang, S. Z. Zard, Org. Lett. 2018, 20, 5304-5308.
K. Endo, T. Ohkubo, T. Shibata, Org. Lett. 2011, 13, 3368-3371.
a) M. J. Hesse, C. P. Butts, C. L. Willis, V. K. Aggarwal, Angew.
Chem. Int. Ed. 2012, 51, 12444-12448; b) X. Y. Li, D. G. Hall, Angew.
Chem. Int. Ed. 2018, 57, 10304-10308; c) M. V. Joannou, B. S.
Moyer, M. J. Goldfogel, S. J. Meek, Angew. Chem. Int. Ed. 2015, 54,
14141-14145.
[22]
a) I. Marek, S. Simaan, A. Masarwa, Angew. Chem. Int. Ed. 2007,
46, 7364-7376; b) M. R. Harris, H. M. Wisniewska, W. H. Jiao, X. C.
Wang, J. N. Bradow, Org. Lett. 2018, 20, 2867-2871; c) L. Dian, I.
Marek, Chem. Rev. 2018, 118, 8415-8434.
[23]
[24]
[25]
[26]
K. Hong, X. Liu, J. P. Morken, J. Am. Chem. Soc. 2014, 136, 10581-
10584.
G. A. Molander, L. N. Cavalcanti, B. Canturk, P. S. Pan, L. E.
Kennedy, J. Org. Chem. 2009, 74, 7364-7369.
Q. I. Churches, J. F. Hooper, C. A. Hutton, J. Org. Chem. 2015, 80,
5428-5435.
using L-tartaric acid with 10m and 10k, gave 11m and 11k with a
low ee % of 10% and > 5% respectively.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901267
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Nivesh Kumar, Reddy Rajasekhar
Reddy, and Ahmad Masarwa*
Page No. – Page No.
Stereoselective Desymmetrization of
gem-diborylalkanes via
“trifluorination”
“3*F-” desymmetrized gem-diboryls: In this work we have developed an efficient
method for the chemo-, regio-, and diastereo-selective synthesis of gem-
diborylalkanes. It is based on a novel late-stage desymmetrization method via
nucleophilic “trifluorination”; it gains access to chiral gem-diborylalkanes possessing
trifluoroborate salts. The knowledge gained provided us with an in-depth
understanding of their reactivity for additional transformations. This enabled us to
develop optimized reaction conditions for their BF3 functionalization.
This article is protected by copyright. All rights reserved.